The use of porphyrin-type photosensitizers for the selective destruction of, for example, cancer cells in animal subjects has been known for several decades. The initial work utilized a mixture of porphyrins prepared from hematoporphyrin by treatment of this starting material with a mixture of sulfuric and acetic acids to result in a composition known specifically as hematoporphyrin derivative (HPD). (See, for example, "Porphyrin Photosensitization" Kessel, D., et al., eds. (1983) Plenum Press.)
HPD and related porphyrin-type photosensitizers appear to localize in malignant cells at the expense of normal tissues. The cells in which the HPD has been accumulated can then be irradiated using light of an appropriate wavelength absorbed by the HPD. When irradiated, the HPD and related photosensitizers have two properties which make them useful. First, when irradiated with the appropriate wavelength, the compounds are capable of fluorescence and can thus be used to detect cells in which they are accumulated (see, for example, Kessel, D., et al., (supra); Gregory, H. B., Jr., et al., Ann Surg (1968) 167:827-829). Second, HPD and its relatives discussed below are useful in therapeutic methods because when irradiated with visible light, a cytotoxic affect on the cells in which they are localized is exerted (see, for example, Diamond, I., et al., Lancet (1972) 2:1175-1177; Dougherty, T. J., et al., Cancer Research (1978) 38:2628-2635; Dougherty, T. J., et al., "The Science of Photomedicine" (1982), J. D. Regan and J. A. Parrish, eds.; Dougherty, T. J., et al., Cancer: Principles and Practices of Oncology (1982) B. T. DeVita Jr. et al., eds.) An improved photosensitizer which is prepared from HPD by adjustment of pH to cause aggregation and recovery of the aggregate is disclosed in U.S. Pat. No. 4,649,151, incorporated herein by reference. The "purified" form of the mixture is called dihematoporphyrin ether (DHE) in the patent and is marketed under the trademark Photofrin.RTM. II. This has been used, as described in U.S. Pat. No. 4,649,151 in a manner completely analogous to HPD.
Other porphyrin-type photosensitizers have also been reported, including various chlorophyll derivatives derived from both bacteria and higher plants. A group of compounds of particular interest is that described as green porphyrins (Gp) in copending U.S. application 414,201 filed Sep. 28, 1989, now U.S. Pat. No. 5,095,030 assigned to the same assignee, and incorporated herein by reference. These compounds are so designated because they absorb light at longer wavelengths than that absorbed by hematoporphyrin derivative or its related compounds, and therefore these porphyrins appear green in white light. The green porphyrins are derived from protoporphyrin-IX by a reaction with a single acetylenic dienophile in a Diels-Alder reaction, and optional subsequent rearrangement and/ or reduction. A subset of green porphyrins, designated herein benzoporphyrin derivatives (BPD) are particularly useful among this group.
All of the porphyrin-type photosensitizing compounds described in the literature are generally useful in the same manner as hematoporphyrin derivative as set forth in the above-cited art. In addition, however, to in vivo therapeutic and diagnostic protocols for tumors, as described above, these compounds can be used in other in vivo and in vitro applications. For example, these photosensitizers are useful in the detection of atherosclerotic plaques as described in U.S. Pat. Nos. 4,512,762 and 4,577,636. U.S. Pat. Nos. 4,500,507 and 4,485,806 describe the use of radiolabeled porphyrin compounds, including HPD, for tumor imaging. U.S. Pat. No. 4,753,958 describes the use of topical applications of porphyrin sensitizers for diagnosis and treatment of skin diseases. U.S. Pat. No. 4,748,120 describes the use of photosensitizers in the treatment of whole blood or blood components to rid them of infectious agents. Photochemical decontamination treatment of blood and components is also described in U.S. Pat. No. 4,727,027 where the photosensitizer is furocoumarin and its derivatives, rather than porphyrin-type materials. In addition, viruses are inactivated in therapeutic protein compositions in vitro as disclosed in U.S. Pat. No. 4,268,947.
For the administration of the porphyrin related photosensitizers in in vivo applications, various pharmaceutical compositions have been suggested. In one approach, the photosensitizing drug was coupled to antibodies which putatively enhance the ability of the drug to localize in the desired target cell. For instance, HPD was coupled to antibodies directed to the murine myosarcoma cell line M1 as described by Mew, D., et al., J Immunol (1983) 130:1473-1477. HPD was also conjugated to CAMAL-1 antibodies which are directed to a human leukemia antigen (Mew, D., et al., Cancer Research (1985) 45:4380-4386). The conjugation of chlorin e.sub.6 to anti T-cell monoclonal antibody was described by Oseroff, A. R., et al., Proc Natl Acad Sci USA (1986) 83:8744-8748.
The use of liposomes or lipoproteins as pharmaceutical excipients for hematoporphyrins and related compounds has also been described. In addition, conventional pharmaceutical excipients have been used; however, the ability to administer significant amounts of photosensitizing drug in a relatively small volume of composition is impaired by the intrinsic water insolubility of most of these compounds. The present invention provides a means to solubilize these photosensitizers in a manner which permits ready administration while having no adverse effects on the accumulation on these materials in target cells or viruses or on the ability of the photosensitizing agent to absorb the appropriate radiation and exert cytotoxic effects or be detectable by fluorescence.